Cracking the cryptic code in amyotrophic lateral sclerosis and frontotemporal dementia: Towards therapeutic targets and biomarkers
Abstract Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two devastating human neurodegenerative diseases. A hallmark pathological feature of both diseases is the depletion of the RNA‐binding protein TDP‐43 from the nucleus in the brain and spinal cord of patients. A major...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-05-01
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| Series: | Clinical and Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/ctm2.818 |
| _version_ | 1811339285183332352 |
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| author | Tetsuya Akiyama Yuka Koike Leonard Petrucelli Aaron D. Gitler |
| author_facet | Tetsuya Akiyama Yuka Koike Leonard Petrucelli Aaron D. Gitler |
| author_sort | Tetsuya Akiyama |
| collection | DOAJ |
| description | Abstract Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two devastating human neurodegenerative diseases. A hallmark pathological feature of both diseases is the depletion of the RNA‐binding protein TDP‐43 from the nucleus in the brain and spinal cord of patients. A major function of TDP‐43 is to repress the inclusion of cryptic exons during RNA splicing. When it becomes depleted from the nucleus in disease, this function is lost, and recently, several key cryptic splicing targets of TDP‐43 have emerged, including STMN2, UNC13A, and others. UNC13A is a major ALS/FTD risk gene, and the genetic variations that increase the risk for disease seem to do so by making the gene more susceptible to cryptic exon inclusion when TDP‐43 function is impaired. Here, we discuss the prospects and challenges of harnessing these cryptic splicing events as novel therapeutic targets and biomarkers. Deciphering this new cryptic code may be a touchstone for ALS and FTD diagnosis and treatment. |
| first_indexed | 2024-04-13T18:24:06Z |
| format | Article |
| id | doaj.art-f94bd40d81034c95a10c574f12b94077 |
| institution | Directory Open Access Journal |
| issn | 2001-1326 |
| language | English |
| last_indexed | 2024-04-13T18:24:06Z |
| publishDate | 2022-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Medicine |
| spelling | doaj.art-f94bd40d81034c95a10c574f12b940772022-12-22T02:35:19ZengWileyClinical and Translational Medicine2001-13262022-05-01125n/an/a10.1002/ctm2.818Cracking the cryptic code in amyotrophic lateral sclerosis and frontotemporal dementia: Towards therapeutic targets and biomarkersTetsuya Akiyama0Yuka Koike1Leonard Petrucelli2Aaron D. Gitler3Department of Genetics Stanford University School of Medicine Stanford California USADepartment of Neuroscience Mayo Clinic Jacksonville Florida USADepartment of Neuroscience Mayo Clinic Jacksonville Florida USADepartment of Genetics Stanford University School of Medicine Stanford California USAAbstract Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two devastating human neurodegenerative diseases. A hallmark pathological feature of both diseases is the depletion of the RNA‐binding protein TDP‐43 from the nucleus in the brain and spinal cord of patients. A major function of TDP‐43 is to repress the inclusion of cryptic exons during RNA splicing. When it becomes depleted from the nucleus in disease, this function is lost, and recently, several key cryptic splicing targets of TDP‐43 have emerged, including STMN2, UNC13A, and others. UNC13A is a major ALS/FTD risk gene, and the genetic variations that increase the risk for disease seem to do so by making the gene more susceptible to cryptic exon inclusion when TDP‐43 function is impaired. Here, we discuss the prospects and challenges of harnessing these cryptic splicing events as novel therapeutic targets and biomarkers. Deciphering this new cryptic code may be a touchstone for ALS and FTD diagnosis and treatment.https://doi.org/10.1002/ctm2.818ALSFTDTDP‐43UNC13A |
| spellingShingle | Tetsuya Akiyama Yuka Koike Leonard Petrucelli Aaron D. Gitler Cracking the cryptic code in amyotrophic lateral sclerosis and frontotemporal dementia: Towards therapeutic targets and biomarkers Clinical and Translational Medicine ALS FTD TDP‐43 UNC13A |
| title | Cracking the cryptic code in amyotrophic lateral sclerosis and frontotemporal dementia: Towards therapeutic targets and biomarkers |
| title_full | Cracking the cryptic code in amyotrophic lateral sclerosis and frontotemporal dementia: Towards therapeutic targets and biomarkers |
| title_fullStr | Cracking the cryptic code in amyotrophic lateral sclerosis and frontotemporal dementia: Towards therapeutic targets and biomarkers |
| title_full_unstemmed | Cracking the cryptic code in amyotrophic lateral sclerosis and frontotemporal dementia: Towards therapeutic targets and biomarkers |
| title_short | Cracking the cryptic code in amyotrophic lateral sclerosis and frontotemporal dementia: Towards therapeutic targets and biomarkers |
| title_sort | cracking the cryptic code in amyotrophic lateral sclerosis and frontotemporal dementia towards therapeutic targets and biomarkers |
| topic | ALS FTD TDP‐43 UNC13A |
| url | https://doi.org/10.1002/ctm2.818 |
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